The National Cancer Institute estimates that 232,000 new cases of prostate cancer will be diagnosed this year. Thirty thousand men will die of the disease and 15 billion dollars will be spent for screening, diagnosis, treatment, and research. Prostate cancer is lethal only when it spreads to other organs. Preventing the spread of prostate cancer would significantly reduce the morbidity and mortality associated with this disease. In order to disseminate to other organs, prostate cancer cells must acquire the ability to detach from the tumor and to attach to components of the tissue that surrounds them. Detachment from the main tumor and attachment to the surrounding tissue involves cell surface adhesion molecules that act to either hold tumor cells together or that facilitate interaction of cells with the extra-cellular matrix (ECM). A balance between these two opposing forces is required to maintain tumors in a non-invasive state. A switch in this balance away from cell-cell cohesion and towards cell-ECM adhesion would promote cancer cell invasion. Maintaining this balance of forces, or reversing it towards cell-cell adhesion could potentially be useful in maintaining tumor integrity and reducing invasive and metastatic potential of prostate cancer. The central theme of this grant is to better understand how these forces influence invasion and to determine whether it will be possible to genetically or pharmacologically alter them in favor of invasion suppression. Forces generated by cell-cell and cell-ECM adhesion, and the molecules which give rise to them, impart to tumors mechanical properties that can be accurately measured. We have previously shown that one such property, tumor cohesivity (TC), is not only strongly correlated with invasiveness of various cancers, but is also a fundamental driving force mediating interactions between tumor cells and the surrounding tissues into which they invade. We have developed methods to accurately measure TC and to discriminate between high and low affinity interactions between tumor and stromal cells. Tissue surface tensiometry (TST) exploits the liquid-like behavior of tumor tissue to measure a key regulator of invasion, namely, tumor cohesivity (TC). We discriminate between low and high affinity interactions using a model based on the observation that when mixed together, cells which do not recognize one another do not remain mixed, but rather, sort-out into two separate phases, whereas cells that have a high affinity for one another tend to remain intermixed. This behavior can be explained using the same physical principles underlying the mixing of liquids. Ethanol and water intermix because they have high affinity for one another, whereas oil and water separate because the affinity of water for itself or oil for itself is greater than that of oil for water. In liquids, affinity is a reflection of the balance between surface and interfacial tension. In cellular systems, these two parameters are a reflection of how strongly cells interact with their own kind, relative to how strongly they interact to other types of cells. This proposal has three objectives. First, we will determine whether TC measurements correlate with invasiveness. Second, we will explore how manipulating particular molecular components leads to associated alterations in TC and invasiveness. Third, we will investigate how TC regulates tumor-stromal interaction. Devising strategies aimed at altering tumor cohesion, maintaining or even restoring compartmentalization between tumor and stromal cells and reducing invasion, are critical to successful treatment of prostate cancer. This proposal aims to elucidate the role of cohesion, not only as a force holding tumor cells together, but also as a regulator of establishing specific spatial relationships between tumor and stromal cells. The information generated will establish a connection between tumor rheology and its molecular underpinnings. Successful completion of these aims will enhance our knowledge of how physical interactions between cancer cells and their surrounding tissue influence invasion.